Ghrelin Fights Sepsis Muscle Loss Through a Brain-Body Signaling Circuit

Sepsis is a leading cause of ICU mortality, and the rapid skeletal muscle wasting it triggers prolongs ventilator dependence, impairs rehabilitation, and worsens survival. Despite its clinical importance, the neuroendocrine mechanisms driving this catabolism are poorly understood, and targeted therapies are absent. This study tests whether the gut-derived hormone ghrelin—known to regulate appetite and energy balance—can combat sepsis-induced muscle loss through a central hypothalamic circuit.

Adult male Sprague–Dawley rats underwent cecal ligation and puncture (CLP), a gold-standard polymicrobial sepsis model. Ghrelin was delivered either subcutaneously (50 or 100 µg/kg every 12 hours) or directly into the third ventricle (3V) via cannula. Hypothalamic JAK2/STAT3 signaling was pharmacologically inhibited with AG490 or activated with colivelin via 3V injection. Adeno-associated virus vectors were used to knock down or overexpress hypothalamic AgRP bilaterally in the arcuate nucleus. An enteral nutrition (EN) arm used intragastric peptison every 12 hours. Readouts included muscle atrophy gene expression (MuRF1, MAFbx), muscle fiber cross-sectional area (CSA), serum IGF-1, IL-6, 3-methylhistidine (3-MH), circulating ghrelin, and hypothalamic GHSR-1a, AgRP, POMC, CART, and IL-1β mRNA, plus phospho-JAK2/STAT3 protein levels.

Key findings: High-dose subcutaneous ghrelin reduced MuRF1 and MAFbx expression by ~37% and ~47% respectively versus untreated CLP rats, increased muscle fiber CSA by ~22%, elevated hypothalamic GHSR-1a and AgRP mRNA, raised serum IGF-1, and suppressed hypothalamic JAK2/STAT3 activation and IL-1β. Direct 3V ghrelin injection reproduced these effects, confirming a central mechanism. Inhibiting AgRP expression had little independent effect on atrophy markers or JAK2/STAT3 activity, but it abolished ghrelin's protective benefit, indicating AgRP acts downstream of ghrelin. Conversely, AgRP overexpression alone modestly reduced muscle atrophy without altering JAK2/STAT3 or hypothalamic inflammation. Blocking JAK2/STAT3 with AG490 in CLP rats partially restored AgRP, reduced IL-1β, and attenuated muscle wasting—an effect that was lost when AgRP was simultaneously knocked down. Crucially, activating JAK2/STAT3 with colivelin in healthy sham animals reproduced the hypothalamic neuropeptide dysregulation and peripheral muscle wasting seen in sepsis. EN elevated circulating ghrelin, boosted hypothalamic AgRP, reduced atrophy gene expression, and increased muscle CSA—but all these benefits vanished in AgRP-knockdown animals.

The mechanistic picture that emerges is a hypothalamic inflammation → JAK2/STAT3 activation → AgRP suppression → peripheral muscle catabolism axis. Ghrelin, whether endogenously stimulated by EN or exogenously administered, engages GHSR-1a on arcuate AgRP neurons, dampens JAK2/STAT3 signaling, and restores AgRP expression to attenuate muscle protein breakdown likely via IGF-1 upregulation.

This work provides the first evidence linking enteral nutrition's muscle-protective effects to a ghrelin–hypothalamic AgRP circuit, offering new mechanistic rationale for early EN in septic patients and identifying central JAK2/STAT3 inhibition and AgRP modulation as potential therapeutic targets.